High purity therapeutic bone agents

ABSTRACT

This invention relates to radioactive, bone-seeking, pharmaceutical methods, compositions and formulations that have a lower impurity profile, a longer shelf life, improved availability and are less expensive to prepare. The compositions of this invention can be conveniently prepared in a timely manner resulting in improved availability and delivery of the drugs to patients.

BACKGROUND OF THE INVENTION Field of the Invention

This invention relates to bone-seeking radioactive metal-chelantcompositions that are suitable for administration to a Patient having:bone pain; one or more calcific tumors; or in need of a bone marrowsuppression procedure.

Description of Related Art

Radiopharmaceuticals based on metal-chelant complexes have been used todiagnose and treat bone cancer. For example, Quadramet® (trademark ofLantheus Medical Imaging, Inc.) is a commercially available chelateformed between Sm-153 and ethylene-diaminetetramethylenephosphonic acid(EDTMP) that is currently indicated for the pain associated with bonemetastases (U.S. Pat. No. 4,898,724). Typical dosages are 1 mCi ofSm-153 per kg body weight of the patient. Thus for a 70 kg patient thedosage would be 70 mCi.

U.S. Pat. No. 5,059,412 teaches the use of Sm-153, Gd-159, Ho-166,Lu-177 and Yb-175 chelates with chelants derived from the1,4,7,10-tetraazacyclododecane moiety including1,4,7,10-tetraazacyclododecanetetramethylenephosphonic acid (DOTMP),while

U.S. Pat. No. 5,064,633 teaches the above metals plus Y-90. Compositionsof Sm, Gd, Ho, Lu and Y with DOTMP comprising predominatelynon-radioactive metal with the corresponding radioactive metal (e.g.Sm-152 with Sm-153 at μCi levels) were prepared and biodistribution datain rats was obtained.

A therapeutically effective biodistribution (fate of the activity afteradministration) for a therapeutic bone agent includes high bone uptake,low soft tissue uptake, rapid clearance of the activity not associatedwith bone, and high lesion-to-normal bone ratio. Compositions that donot have these characteristics are detrimental to the patient. Forexample, high soft tissue uptake would result in the patient receiving ahigh radiation dose to the liver, bone marrow or other soft tissueleading to undesirable side effects.

Radionuclides such as Sm-153 are prepared in a nuclear reactor bybombarding purified targets of the element containing one less neutronand in the process generate radionuclidic impurities. For example, toproduce Sm-153 the target that is irradiated is Sm-152. When Sm-153decays, Eu-153 is formed and an unwanted impurity, radioactive Eu-154 isformed from neutron capture by Eu-153.

The impurities can be detrimental to institutions from both a patientand a waste disposal standpoint. For example, too much Eu-154administered to a patient would result in the isotope giving anundesirable dose to a patient for a long period of time because of itshalf-life of 8.8 years. In addition, the dose that is excreted in theurine by the patient containing Eu-154 is a concern and institutions maybe forced to collect the radioactive urine. Disposal of the productvials containing residual activity can be a problem. These vials andsyringes are typically allowed to decay for 10 half-lives prior todisposal. This is a reasonable amount of time for Sm-153 (about 20 days)but not for Eu-154 (about 88 years). Processes must be implemented inorder to deal with waste disposal of vials and syringes that are used.This makes the use of these types of radiopharmaceuticals more complexand institutions may chose not to use the drugs.

In addition, these long-lived impurities cause issues with theradioactive licensing process for the institution. Typicallyinstitutions are only allowed small amounts of long-lived radionuclides(having half-lives greater than 120 days) before they are required tohave financial assurance. Financial assurance can be very expensiveespecially for institutions that only handle short-lived isotopes.

The specifications for Quadramet® call for the product to contain lessthan 0.093 microcuries (μCi) of Eu-154 per millicurie (mCi) of Sm-153 atExpiration Date(http://health.phys.iit.edu/extended_archive/0001/msg00922.html,http://acnp-cal.org/SM153INS.html) or 4 days from the manufacture date(http://www.ibamolecular.eu/products/quadramet). This restriction limitsthe expiration time of the drug. Since Sm-153 decays faster than Eu-154,the longer the Sm-153 solution decays, the higher the amount of Eu-154in the sample relative to Sm-153. Thus expiration of not only formulatedQuadramet® (e.g. Ca-EDTMP+Sm-153) but also the Sm-153 used to produceQuadramet® is limited by the amount of Eu-154 in the sample.

In nuclear reactors such as the one at the University of Missouri inColumbia, Mo., the Sm-152 samples are irradiated for one week in the“flux trap” in order to produce the high specific activity Sm-153required for the production of Quadramet®. The flux trap is onlyaccessed once a week and therefore high specific activity Sm-153 canonly be produced on a weekly basis. Because of the growing amount ofEu-154 compared to Sm-153, the isotope can only be used for a shortperiod of time. Thus the drug is not available to treat patients on somedays of the week. The flux trap portion of the reactor is also the mostexpensive to access (requiring reactor shut-down), thus increasing theproduction cost of the isotope.

Clearly, there is a need for a product with a longer shelf life and abetter impurity profile.

BRIEF SUMMARY OF THE INVENTION

The present invention provides a method for the treatment of a Patientcomprising administration to the Patient having bone pain, one or morecalcific tumors, or in need of a bone marrow suppressing procedure, apharmaceutically-acceptable formulation of a chelate compositioncomprising a Clinically Relevant Dosage of the composition that istherapeutically effective, said composition possessing an extendedExpiration Date of greater than or equal to about 5 days and saidchelate comprises Sm-153 and DOTMP or a physiologically-acceptable saltthereof wherein the Sm-153 dosage is at least 35 mCi.

The formulation of this invention comprises a chelate composition eitheras a pre-mixed drug ready for use or a kit having two separatecomponents, the chelant and the isotope, which components are mixed toform the chelate composition at the appropriate time prior to use in themethod.

Also provided is the chelate composition comprising a ClinicallyRelevant Dosage of the composition that is therapeutically effective andpharmaceutically-acceptable, said composition possessing an extendedExpiration Date of greater than or equal to about 5 days and saidchelate comprises Sm-153 and DOTMP or a physiologically-acceptable saltthereof wherein the Sm-153 dosage is at least 35 mCi.

DETAILED DESCRIPTION OF THE INVENTION

It is understood that the terminology used herein is for the purpose ofdescribing particular embodiments only and is not intended to belimiting. As used in this specification, the singular forms “a”, “an”,and “the” include plural referents unless the content clearly indicatesotherwise. The following terms in the Glossary as used in thisapplication are to be defined as stated below and for these terms, thesingular includes the plural.

Various headings are present to aid the reader, but are not theexclusive location of all aspects of that referenced subject matter andare not to be construed as limiting the location of such discussion.

Also, certain US patents and PCT published applications have beenincorporated by reference. However, the text of such patents is onlyincorporated by reference to the extent that no conflict exists betweensuch text and other statements set forth herein. In the event of suchconflict, then any such conflicting text in such incorporated byreference US patent or PCT application is specifically not soincorporated in this patent.

Glossary

% means weight percent, unless stated otherwise

Clinically Relevant Dosage means enough activity to cause either painpalliation or reduction of tumor burden. This dosage is about 0.5 mCiper kg body weight or about 35 mCi for a 70 kg patient; more preferred1.0 mCi per kg body weight or about 70 mCi for a 70 kg patient. Higheramounts of radioactivity may be administered to the patients or fortreating tumor regression or bone marrow ablation in patients.

DOTMP means 1,4,7,10-tetraazacyclododecanetetramethylenephosphonic acid

EDTMP means ethylenediaminetetramethylenephosphonic acid

Expiration Date means the number of days after production when a Sm-153bone agent formulation contains equal to or greater than 0.093microcuries of Eu-154 per mCi of Sm-153.

FDA means US Food and Drug Administration including its regulations

Patient means an animal or human in need of treatment

Ci means curies

μCi means microcuries

mCi means millicuries

Discussion

The specific activity of an isotope is sometimes a source of confusionbecause it is expressed in many ways (see Practical Aspects of labelingDTPA and DOTA peptides with Y-90, In-111, Lu-177 and Ga-68 forPeptide-Receptor Scintigraphy and peptide-Receptor Radionuclide Therapyin preclinical and Clinical Applications(http://pharmacyce.unrmedu/program_information/freelessonfiles/Vol16Lesson5.pdf).

For this invention, the specific activity of an isotope is defined asthe radioactivity of the isotope in question divided by the mass of allof the isotopes (stable and radioactive) of that element. For examplefor reactor produced Sm-153 where the starting material is Sm-152 thatis converted to Sm-153, the specific activity of Sm-153 is the amount ofradioactivity of Sm-153 in the sample divided by the total mass of Sm inthe sample (e.g. activity Sm-153/sum of masses of Sm-152 and Sm-153).The units of the number are typically in Curies per gram (Ci/g) ormilliCuries per milligram (mCi/mg). In some cases the percent of theisotope that is radioactive is reported. For example in reactor producedSm-153, only about 2% of the Sm is Sm-153 and about 98% isnon-radioactive Sm-152.

Traditionally, nuclear medicine scientists strive to increase thespecific activity of the isotopes of interest. For example, twogovernment grants for providing high specific activity isotopes havebeen recently granted (High Specific Activity Sm-153 by Post IrradiationIsotope Separation, DOE SBIR grant Solicitation Number DE-FOA-0000676,Production of Commercial High Specific Activity Sn-117m Radiochemicaland Chelates, DOE grant Solicitation Number DE-FOA-000782). The use ofhigh specific activity isotopes allows for less mass of the elementneeded to achieve the same amount of radioactivity. This leads to loweramounts of chelating agents and/or proteins needed in the radioactivedrug. In addition, in many cases such as with labeled antibodies andproteins, the receptors on cells (such as cancer cells) that the drugstarget are limited. If the specific activity of the isotope is low (e.g.2% of the atoms are radioactive), then the amount of active drug thatreaches the target is relatively small. However, if the specificactivity is high (e.g. 100% of the atoms are radioactive), then theamount of effective drug that reaches the target is much higher, whichexplains why so much effort is put forth in radioisotope production toachieve higher and higher specific activity.

Contrary to this conventional wisdom where higher specific activityisotopes are sought-after as desirable, this invention utilizes Sm-153produced in a lower flux portion of the nuclear reactor for a shorterperiod of time, resulting in a lower specific activity isotope with asignificant cost reduction and lower impurity profile. When combinedwith DOTMP a product can be produced which comprises a ClinicallyRelevant Dosage of Sm-153-DOTMP with a reduced radionuclidic impurityprofile, a longer shelf life, a lower cost to manufacture, and can bemade available to patients on a more frequent basis.

The formulations of the present invention may be in a kit form such thatthe two components (chelant and isotope) are mixed at the appropriatetime prior to use or provided pre-mixed as the ready to use drug.Whether pre-mixed as the drug or as a kit where the drug is made onsite, the formulations require a pharmaceutically-acceptable carrier.Such carriers comprise any suitable pharmaceutically-acceptable carriersuch as one or more of a suitable solvent, preservatives, diluents,excipients and buffers. Useful solvents include, for example, water,aqueous alcohols and glycols. The formulation is administered to thePatient by injection intravenously or intramuscularly.

The invention will be further clarified by a consideration of thefollowing examples, which are intended to be purely exemplary of theinvention.

Materials and Equipment

The radioactive isotopes were purchased from The University of MissouriResearch Reactor.

Chelants were purchased from commercial sources or were prepared asdescribed in U.S. Pat. No. 5,059,412.

General Procedure

In the following examples, the lettered examples are comparative, andthe numbered examples are this invention.

Example A: Comparative

A Quadramet® formulation containing 105 mg of EDTMP and 150 mCi ofSm-153 was prepared. This quantity is normally enough to treat 2patients weighing 70 kg at a 1 mCi/kg dosage. Sm-153 is prepared byirradiating Sm-152 in a nuclear reactor for 155 hours with a thermalneutron flux of 2.20 x 10¹⁴ neutrons/cm²-sec. The specific activity ofthe Sm-153 is 6,650 mCi/mg at end of irradiation and contains 0.0181 μCiof Eu-154 per mCi of Sm-153. After 5 days of radioactive decay however,the specific activity of the Sm-153 is 1,102 mCi/mg but the activity ofthe Eu-154 impurity is 0.1092 μCi Eu-154 per mCi of Sm-153. This exceedsthe FDA allowable amount of Eu-154 (0.093 μCi of Eu-154 per mCi ofSm-153) by 17%. A Quadramet formulation prepared by combining 150 mCi ofthis decayed Sm-153 with EDTMP contains 16.38 μCi of Eu-154 (0.1092 μCiof Eu-154 per mCi Sm-153) and is thus out of spec and can no longer beused.

Example B: Comparative

Sm-153 is prepared by irradiating Sm-152 in a nuclear reactor for 48hours with a thermal neutron flux of 8.00×10¹³ neutrons/cm²-sec. Thespecific activity of the Sm-153 is 1,430 mCi/mg at end of irradiationand contains 0.0005 μCi of Eu-154 per mCi of Sm-153. After 5 days ofradioactive decay, the specific activity of the Sm-153 is 237 mCi/mg andthe the activity of the Eu-154 impurity is 0.00296 μCi of Eu-154 per mCiof Sm-153. This is below the FDA allowable amount of Eu-154 (0.093 μCiof Eu-154 per mCi of Sm-153). However, the Quadramet® formulationrequires a minimum EDTMP to Sm mole ratio of 273:1 in order to properlycontrol the biodistribution of Sm-153 (calculated from the data inQuadramet® package insert). Because of this requirement the maximum massof Sm used in a Quadramet preparation is about 0.134 mg. Therefore at aspecific activity of 237 mCi/mg only about 32 mCi can be prepared. Thisis not a sufficient dosage to treat a 70 kg patient at 1 mCi/kg or evena 70 kg patient at 0.5 mCi/kg.

EXAMPLE 1

Sm-153 is prepared by irradiating Sm-152 in a nuclear reactor for 48hours with a thermal neutron flux of 8.00×10¹³ neutrons/cm²-sec. Thespecific activity of the Sm-153 is 1,430 mCi/mg at end of irradiationand contains 0.0005 μCi of Eu-154 per mCi of Sm-153. After 5 days thespecific activity is 0.237 Ci/mg and the activity of the impurity Eu-154is 0.00296 μCi Eu-154 per mCi of Sm-153. This is 3.2% of the FDAallowable maximum amount of Eu-154. Since Sm-153-DOTMP can be preparedusing a 1:1 mole ratio of DOTMP to Sm, a preparation using 10 mg ofDOTMP and 657 mCi (2.77 mg Sm) of the 5 day old Sm-153 is made. Thiscomposition produces sufficient quantities of Sm-153 to treat 9 patientsweighing an average of 70 kg at 1 mCi/kg and has an Expiration Date ofgreater than 5 days.

EXAMPLE 2

A formulation, prepared as in Example 1, is allowed to decay 10 days.The amount of Sm-153 in the formulation is now 110 mCi which issufficient to treat one patient with a weight of 70 kg at 1 mCi ofSm-153 per kg body weight. The formulation contains 0.0178 μCi of Eu-154per mCi of Sm-153 which is 19% of the allowable amount of Eu-154.Therefore, the composition has a greater than 10 day Expiration Date.

EXAMPLE 3

A formulation, prepared as in Example 1, is allowed to decay 13 days.The amount of Sm-153 in the formulation is now 37 mCi which issufficient to treat one patient with a weight of 70 kg at 0.5 mCi ofSm-153 per kg body weight. The formulation contains 0.05228 μCi ofEu-154 per mCi of Sm-153 which is 56% of the allowable amount of Eu-154.Therefore, the formulation has a greater than 13 day Expiration Date.

Although the invention has been described with reference to itspreferred embodiments, those of ordinary skill in the art may, uponreading and understanding this disclosure, appreciate changes andmodifications which may be made which do not depart from the scope andspirit of the invention as described above or claimed hereafter.Accordingly, this description is to be construed as illustrative onlyand is for the purpose of teaching those skilled in the art the generalmanner of carrying out the invention.

1. A method for the treatment of a Patient comprising administration tothe Patient having bone pain, one or more calcific tumors, or in need ofa bone marrow suppressing procedure, a pharmaceutically-acceptable,formulation of a chelate composition comprising a Clinically RelevantDosage of the composition that is therapeutically effective, saidcomposition either: i) has said formulation as a chelate compositionconsisting essentially of Sm-153 and DOTMP or aphysiologically-acceptable salt thereof, or ii) has said formulationcomprising a kit containing as two separate components, the DOTMPchelant and the Sm-153 isotope, which components are mixed to form thechelate composition at the appropriate time prior to use, wherein theSm-153 isotope possesses an extended Expiration Date of greater than orequal to about 5 days, and wherein the Sm-153 dosage is at least 35 mCi;with the proviso that the chelate composition is prepared by a processcomprising the steps of: a) irradiating Sm-152 in a lower flux portionof the nuclear reactor having less than 8.5×1013 neutron/cm²-sec to formlow specific activity Sm-153, wherein the isotope composition after theirradiation contains mainly Sm-152 and Sm-153 with reduced traceimpurity of Eu-154 less than 0.093 μCi Eu-154/mCi Sm-153 after 5 days ofdecay, thereby providing an extended Expiration Date greater than orequal to about 5 days; b) taking the prepared isotope mixture from stepa) and either using it in step c) or allowing it to decay and then usingit in step c) which decay further lowers the specific activity of theSm-153 formed in step a) while maintaining less than 0.093 μCi of Eu-154per mCi of Sm-153; and c) reacting DOTMP or a physiologically-acceptablesalt thereof as the chelant with the Sm-153 isotope mixture from step b)in an aqueous solvent to form the radioactive chelate composition thatis pharmaceutically-acceptable and has a Clinically Relevant Dosage thatis therapeutically effective.
 2. (canceled)
 3. The method of claim 1wherein the dosage of Sm-153 is about 70 mCi or more.
 4. The method ofclaim 1 wherein the Expiration Date is about 10 days or more.
 5. Themethod of claim 1 wherein the formulation has a reduced radionuclidicimpurity profile, and a longer shelf life.
 6. The method of claim 5wherein the formulation has a reduced radionuclidic impurity profilewhich contains less than 0.093 μCi of Eu-154 per mCi of Sm-153 atExpiration Date.
 7. The method of claim 1 wherein the ClinicallyRelevant Dosage is about 0.5 mCi per kg body weight or about 35 mCi fora 70 kg patient.
 8. The method of claim 1 wherein the ClinicallyRelevant Dosage is about 10 mCi per kg body weight or about 70 mCi for a70 kg patient.
 9. The method of claim 1 wherein thepharmaceutically-acceptable formulation comprises one or more of anaqueous solvent, preservatives, diluents, excipients and buffers. 10.(canceled)
 11. The method of claim 1 wherein the Patient has theformulation injected intravenously.
 12. A pharmaceutically-acceptablechelate composition comprising a Clinically Relevant Dosage of thecomposition that is therapeutically effective andpharmaceutically-acceptable, wherein Sm-153 isotope used in the saidchelate composition possessing an extended Expiration Date of greaterthan or equal to about 5 days and said chelate consisting essentially ofSm-153 and DOTMP or a physiologically-acceptable salt thereof, whereinthe Sm-153 dosage is at least 35 mCi; with the proviso that the chelatecomposition is prepared by a process comprising the steps of: a)irradiating Sm-152 in a lower flux portion of the nuclear reactor havingless than 8.5×10¹³ neutron/cm²-sec to form low specific activity Sm-153,wherein the isotope composition after the irradiation contains mainlySm-152 and Sm-153 with reduced trace impurity of Eu-154 less than 0.093μCi Eu-154/mCi Sm-153 after 5 days of decay, thereby providing anextended Expiration Date greater than or equal to about 5 days: b)taking the prepared isotope mixture from step a) and either using it instep c) or allowing it to decay and then using it in step c) which decayfurther lowers the specific activity of the Sm-153 formed in step a)while maintaining less than 0.093 μCi of Eu-154 per mCi of Sm-153; andc) reacting DOTMP or a physiologically-acceptable salt thereof as thechelant with the Sm-153 isotope mixture from step b) in an aqueoussolvent to form the radioactive chelate composition that ispharmaceutically-acceptable and has a Clinically Relevant Dosage that istherapeutically effective.
 13. A pharmaceutical formulation comprising achelate composition comprising a Clinically Relevant Dosage of thecomposition that is therapeutically effective andpharmaceutically-acceptable, Sm-153 used in the said chelate compositionpossessing an extended Expiration Date of greater than or equal to about5 days and said chelate consisting essentially of Sm-153 and DOTMP or aphysiologically-acceptable salt thereof, wherein the Sm-153 dosage is atleast 35 mCi, and a pharmaceutically-acceptable carrier; with theproviso that the chelate composition is prepared by a process comprisingthe steps of: a) irradiating Sm-152 in a lower flux portion of thenuclear reactor having less than 8.5×1013 neutron/cm²-sec to form lowspecific activity Sm-153, wherein the isotope composition after theirradiation contains mainly Sm-152 and Sm-153 with reduced traceimpurity of Eu-154 less than 0.093 μCi Eu-154/mCi Sm-153 after 5 days ofdecay, thereby providing an extended Expiration Date greater than orequal to about 5 days; b) taking the prepared isotope mixture from stepa) and either using it in step c) or allowing it to decay and then usingit in step c) which decay further lowers the specific activity of theSm-153 formed in step a) while maintaining less than 0093 μCi of Eu-154per mCi of Sm-153; and c) reacting DOTMP or a physiologically-acceptablesalt thereof as the chelant with the Sm-153 isotope mixture from step b)in an aqueous solvent to form the radioactive chelate composition thatis pharmaceutically-acceptable and has a Clinically Relevant Dosage thatis therapeutically effective.
 14. The formulation of claim 13 wherein akit comprising two separate components, the DOTMP chelant and the Sm-153isotope, are mixed to form the chelate at the appropriate time prior touse.
 15. The formulation of claim 13 wherein thepharmaceutically-acceptable carrier comprises one or more of an aqueoussolvent, preservatives, diluents, excipients and buffers.
 16. (canceled)17. The formulation of claim 14 wherein the pharmaceutically-acceptablecarrier comprises one or more of an aqueous solvent, preservatives,diluents, excipients and buffers.